Combination of an azetidine LPA1 receptor antagonist with pirfenidone and/or nintedanib for use in the treatment of fibrotic diseases

Patent metadata

Field	Value
Publication number	US-12539294-B2
Application number	US-202017782530-A
Country	US
Kind code	B2
Filing date	Dec 3, 2020
Priority date	Dec 4, 2019
Publication date	Feb 3, 2026
Grant date	Feb 3, 2026

Abstract

The present invention concerns the compounds of formula (I)

wherein R 1 , R 2 , R 3 , X, and Y are as described in the description, and their use as antagonists of the LPA 1 receptor, in combination with one or more therapeutically active ingredients acting as anti-fibrotic agent(s); such as especially pirfenidone and/or nintedanib, in the prevention and/or treatment of fibrotic diseases. The invention further relates to pharmaceutical compositions comprising the compounds of formula (I) in combination with one or more therapeutically active ingredients acting as anti-fibrotic agent(s) such as pirfenidone or nintedanib.

First claim

The invention claimed is:

1 . A method for prophylaxis or treatment of a fibrotic disease in a subject in need thereof, wherein the method comprises administering to the subject a compound of Formula (I):

wherein
X is CH; Y is N; and R 2 is methyl, ethyl, or isopropyl; or
X is N; Y is CH; and R 2 is methyl, ethyl, or isopropyl, or difluoromethyl;

R 1 is fluoro, chloro, bromo, or methyl; and
R 3 represents
—(CH 2 ) 2-3 —C(CH 3 ) 2 —COOH;
—CO—(CH 2 ) 1-2 —C(CH 3 ) 2 —COOH; or
—SO 2 —NH 2 ;

or a pharmaceutically acceptable salt thereof;

wherein said compound of formula (I) is administered in combination with:
pirfenidone, or a pharmaceutically acceptable salt thereof;
nintedanib, or a pharmaceutically acceptable salt thereof; or
both pirfenidone, or a pharmaceutically acceptable salt thereof, and nintedanib, or a pharmaceutically acceptable salt thereof.

2 . The method according to claim 1 , wherein X is CH; Y is N; and R 2 is methyl, ethyl, or isopropyl.

3 . The method according to claim 2 , wherein R 1 is fluoro, chloro, or bromo.

4 . The method according to claim 1 , wherein X is N; Y is CH; and R 2 is difluoromethyl.

5 . The method according to claim 4 , wherein R 1 is methyl.

6 . The method according to claim 1 , wherein R 3 represents
—CH 2 —CH 2 —C(CH 3 ) 2 —COOH; —CO—CH 2 —C(CH 3 ) 2 —COOH; or —SO 2 —NH 2 .

7 . The method according to claim 3 , wherein R 3 represents-SO 2 —NH 2 .

8 . The method according to claim 1 , wherein the compound is
4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid; 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylpentanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 5-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-5-oxopentanoic acid; N-(2-(difluoromethoxy)-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; 3-(2-isopropylphenyl)-N-(2-methoxy-6-methylpyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide; N-(2-ethoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(2-isopropoxy-6-methylpyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; 4-(3-((6-chloro-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((6-chloro-4-ethoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((6-chloro-4-isopropoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((6-bromo-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid; 5-(3-((6-chloro-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylpentanoic acid; 5-(3-((6-chloro-4-ethoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylpentanoic acid; 4-(3-((6-chloro-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 4-(3-((6-bromo-4-methoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; 4-(3-((6-chloro-4-ethoxypyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; N-(6-fluoro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-chloro-4-ethoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-chloro-4-isopropoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; N-(6-bromo-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; or 3-(2-isopropylphenyl)-N-(4-methoxy-6-methylpyridin-3-yl)-1-sulfamoylazetidine-3-carboxamide; or a pharmaceutically acceptable salt thereof.

9 . The method according to claim 1 , wherein the compound is
4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethylbutanoic acid; 4-(3-((2-(difluoromethoxy)-6-methylpyridin-3-yl) carbamoyl)-3-(2-isopropylphenyl) azetidin-1-yl)-2,2-dimethyl-4-oxobutanoic acid; or N-(6-chloro-4-methoxypyridin-3-yl)-3-(2-isopropylphenyl)-1-sulfamoylazetidine-3-carboxamide; or a pharmaceutically acceptable salt thereof.

10 . The method according to claim 1 , wherein said compound of formula (I), or pharmaceutically acceptable salt thereof, is administered in combination with pirfenidone, or a pharmaceutically acceptable salt thereof.

11 . The method according to claim 10 , wherein pirfenidone, or a pharmaceutically acceptable salt thereof, is administered in a pharmaceutical unit dosage form suitable for the oral administration of a total of about 2403 mg per day or below.

12 . The method according to claim 1 ; wherein said fibrotic disease is:
pulmonary fibrosis; renal fibrosis; or liver fibrosis.

13 . The method according to claim 1 ; wherein said fibrotic disease is:
idiopathic pulmonary fibrosis; pulmonary fibrosis secondary to systemic inflammatory disease; pulmonary fibrosis secondary to sarcoidosis; radiation-induced fibrosis; silicosis-induced pulmonary fibrosis; or asbestos-induced pulmonary fibrosis.

14 . A pharmaceutical composition comprising, as active principles, a compound of formula (I):

wherein
X is CH; Y is N; and R 2 is methyl, ethyl, or isopropyl; or
X is N; Y is CH; and R 2 is methyl, ethyl, or isopropyl, or difluoromethyl;

R 1 is fluoro, chloro, bromo, or methyl; and
R 3 represents
—(CH 2 ) 2-3 —C(CH 3 ) 2 —COOH;
—CO—(CH 2 ) 1-2 —C(CH 3 ) 2 —COOH; or
—SO 2 —NH 2 ;

or a pharmaceutically acceptable salt thereof; in combination with one or more therapeutically active ingredients acting as anti-fibrotic agent(s); wherein said anti-fibrotic agent(s) is/are pirfenidone and/or nintedanib; or a pharmaceutically acceptable salt thereof; as well as at least one pharmaceutically acceptable excipient.

15 . The method according to claim 1 , wherein said fibrotic disease is:
pulmonary fibrosis; wherein said pulmonary fibrosis is selected from idiopathic pulmonary fibrosis; pulmonary fibrosis secondary to systemic inflammatory disease; pulmonary fibrosis secondary to sarcoidosis; iatrogenic pulmonary fibrosis; silicosis-induced pulmonary fibrosis; asbestos-induced pulmonary fibrosis; and pleural fibrosis; renal fibrosis; wherein said renal fibrosis is selected from renal fibrosis associated with CKD, chronic renal failure, tubulointerstitial nephritis, and a chronic nephropathy selected from primary glomerulonephritis and glomerulonephritis secondary to a systemic inflammatory disease, diabetes, focal segmental glomerular sclerosis, IgA nephropathy, hypertension, renal allograft, or Alport syndrome; or liver fibrosis; wherein said liver fibrosis is selected from cirrhosis, alcohol-induced liver fibrosis, nonalcoholic steatohepatitis, biliary duct injury, primary biliary cirrhosis, infection-induced liver fibrosis, viral-induced liver fibrosis, and autoimmune hepatitis.

16 . The method according

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Birker Magdalena
• Lescop Cyrille

Classifications

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title

• A61K31/4427 Primary

  containing further heterocyclic ring systems · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61P1/16

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title